Investigation into the combination of PLX2853 with ruxolitinib in patients with intermediate-2 or high risk myelofibrosis not receiving an adequate response with ruxolitinib alone.

• Age> = 16 years. • Primary or secondary myelofibrosis OR Dynamic International Prognostic Scoring System (DIPSS) defined risk groups intermediate-2 or high risk. • Treated with > = 24 weeks of ruxolitinib with ongoing residual splenomegaly > 5cm from costal margin. • Platelets > 75x109/L. • Neutrophils > 1.0x109/L. • < 10% blasts in peripheral blood and/or bone marrow. • Coagulation (INR or PT) and Activated partial thromboplastin time < = 1.5 x ULN. • Albumin > 3.0 g/dL. • Stable dose of ruxolitinib (no dose modifications) established for 4 weeks prior to trial entry. • Except as specified above for organ function, all drug-related toxicity from previous therapy for myelofibrosis must be resolved (to Grade < = 1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI CTCAE v4.0]) prior to study treatment administration (Grade 2: alopecia, hot flashes, decreased libido, or neuropathy is allowed). • Able to provide written informed consent. • Able to comply with trial treatment and follow-up. • Serum total bilirubin < = 2.0 × ULN OR Direct bilirubin < = ULN for patients with total bilirubin > 2.0 × ULN; o Exception for elevated total bilirubin secondary to Gilbert’s disease, in which case it must be < = 3 x ULN. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < = 2.0 × ULN.

• Prior exposure to a bromodomain inhibitor such as OTX-015 or CPI-0610. • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to trial entry). • Patients and partners of childbearing potential (pre-menopausal female capable of becoming pregnant) not willing to use effective contraception from the time of negative pregnancy test during screening to 90 days after the last dose of study drug. • Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for > = 1 year. • Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal treatment. • ECOG Performance Status Score > = 3. • Clinically significant cardiac disease, defined as any of the following: o Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded. o Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval (drugs with a low risk of QTc prolongation that are needed for infection control or nausea may be permitted with approval from the Clinical Coordinator). o QT interval corrected for heart rate using the Fridericia method (QTcF) > = 450 msec males or QTcF > = 470 msec (females) at Screening. o History of clinically significant cardiac disease or congestive heart failure > New York Heart Association Class II. Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months. o Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg which has been confirmed by 2 successive measurements despite optimal medical management. o Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 3 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring > 1 month before the start of study medication). • Inadequate renal function as defined by eGFR or CrCl < = 30 mls/min. • Current active viral hepatitis including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative. Note that elevated levels of biotin may interfere with viral serology testing. • Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry.). • Known or suspected allergy to the investigational agent or any agent given in association with this study. • Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption. • Patient is participating in any other therapeutic clinical study (observational or registry studies are allowed).